This prospective study of genetic prediabetics (offspring of two diabetic parents, or unaffected monozygotic twins with a known diabetic twin mate) moves into its eight year. Approximately 350 subjects are seen 2 to 4 times a year for in depth studies of glucose homeostasis and associated insulin, growth hormone, cholesterol, triglyceride, and glucagon responses. Special attention is focused upon annual oral and intravenous glucose tolerance testing which should document the evolution and the natural history of the beta cell's insulin response as the prediabetic subjects make the transition into chemical and clinical diabetes. In addition, test procedures designed to specifically examine particular hormone responses are being performed such as arginine stimulation of plasma glucagon responses and insulin responses following glucagon administration. The long-term prospective study of the metabolic effect of chronic tolbutamide administration is to be continued. Approximately 35 prediabetic patients were started in this program prior to 1970 and have taken tolbutamide (0.5 gm twice a day). After an initial battery of glucose tolerance tests were performed (viz. Oral glucose, Intravenous glucose, Cortisone-primed oral glucose and Intravenous tolbutamide tests), this sequence of testing has continued during the drug administration period. Acute serum lipid dynamics will be studied during a variety of perturbations. Initial observations suggested a significant reduction of both cholesterol and triglyceride after oral glucose administration. Similar dynamics will be studied after acute intravenous glucose and tolbutamide administration to seek possible mechanisms for this change of serum lipids.